Stage-Dependent Function of Astrocytes in Alzheimer’s Disease: A Review

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), astrogliosis, loss of neurons, and cognitive decline. In this narrative review, we explore astrocytes' dual role in the healthy brain and the brain with AD, reflecting on the available human studies and animal models. Astrocytes are multifunctional regulators of brain homeostasis and neuronal activity within the central nervous system (CNS). These highly plastic cells undergo morphological and functional changes in response to the progression of AD, and exhibit dynamic, stage-dependent phenotypes. In the early stage of AD, astrocytes adopt a predominantly neuroprotective A2 phenotype, marked by enhanced glycolysis, Aβ clearance, anti-inflammatory signaling, and synaptic support. At the intermediate stage, they shift toward an inflammatory phenotype, which consequently impairs metabolism and neurotransmitter uptake. In the late stage of AD, the A1 phenotype, characterized by inflammatory cytokine secretion, complement activation, Ca dysregulation, and mitochondrial toxicity, exacerbates AD progression. Thus, the balance between these subtypes can significantly influence the disease's trajectory, with A1 astrocytes contributing to neurotoxicity and A2 astrocytes providing neuroprotection, especially in the early stages.